GENETICALLY MODIFIED MOUSE MODEL SHARED RESOURCE: PROJECT SUMMARY Construction of transgenic and gene-targeted mice is an essential technology for cancer research, and the Herbert Irving Comprehensive Cancer Center (HICCC) has a long history of leadership in this field. Directed by Franklin Costantini, PhD, a pioneer in transgenic mouse technology, the Genetically Modified Mouse Model Shared Resource (GMMMSR) makes transgenic and gene targeting technologies accessible to HICCC members, generating hundreds of new genetically modified mouse strains. Services include: (1) generation of conventional and large construct (BAC) transgenics, (2) embryonic stem cell targeting and generation of knockout (KO) and knock-in mice, (3) generation of conditional KO mice, and (4) generation of CRISPR- based KO and knock-in strains.These comprehensive services are broadly used by HICCC members for the in vivo functional characterization of oncogenes and tumor supressors. During the current project period (2014-2019), GMMMSR incorporated CRISPR genome editing services to generate mouse lines with deletions, point mutations, and more complicated genetic manipulations such as exon swapping and reporter knock-in. The diversity of services provided and the unique technical expertise, easy accessibility and high cost-effectiveness of the GMMMSR make it the provider of choice for generation of genetically manipulated mouse models by HICCC members. The GMMMSR is invariably ranked as one of the most highly valued resources at Columbia University Irving Medical Center in annual users? surveys. The GMMSR provides services that are not available from commercial sources (e.g., recombinant BAC transgenics) and not easily accessible at other sites, and that are of central importance to the research of numerous HICCC members. The GMMMSR has the capability to engineer novel mouse lines in about 10 months; and CRISPR-based gene targeting services can deliver a new genetically modified line in about three months. In addition, mouse lines generated by GMMMSR are transferred to HICCC members without a lengthy quarantine process, further accelerating and empowering HICCC member research. In addition to these advanced transgenic and gene targeting services, the GMMMSR offers investigators training, advice and assistance in the design of transgenes, gene-targeting vectors and CRISPR gene editing, mouse breeding, and the interpretation of experimental results. The GMMMSR will continue to incorporate novel technologies, to provide state-of-the- art transgenic and gene-editing services, and to promote high value and accessibility through service and consulting, with the goal of empowering the Research Programs of HICCC members. Over the current project period, the capabilities of the GMMMSR were utilized by 39 HICCC members, supported key data and insights for 28 HICCC member peer-reviewed publications, including15 papers with impact factor >10, of which nine are in journals with an impact factor >20 (Nature, Nature Medicine, Cancer Discovery and Cancer Cell), and currently supports research 13 NIH-funded research project grants (10 from NCI).